7crv

Structural highlights

Function

NL1A1_RAT Acts as the sensor component of the Nlrp1a inflammasome, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis (PubMed:33731929). Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation (By similarity). Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as B.anthracis lethal toxin (LT) or Val-boroPro inhibitor, and mediates the formation of the inflammasome polymeric complex (PubMed:20502689, PubMed:31383852, PubMed:33731929). In response to pathogen-associated signals, the N-terminal part of Nlrp1a is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (NACHT, LRR and PYD domains-containing protein 1a, C-terminus), which polymerizes to initiate the formation of the inflammasome complex: the inflammasome directly recruits pro-caspase-1 (proCASP1) independently of PYCARD/ASC and promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), leading to pyroptosis (By similarity). In the absence of GSDMD expression, the Nlrp1a inflammasome is able to recruit and activate CASP8, leading to activation of gasdermin-E (GSDME) (By similarity).[UniProtKB:Q2LKU9][UniProtKB:Q2LKW6][UniProtKB:Q9C000]^{[1] [2] [3]} Constitutes the precursor of the Nlrp1a inflammasome, which mediates autoproteolytic processing within the FIIND domain to generate the N-terminal and C-terminal parts, which are associated non-covalently in absence of pathogens and other damage-associated signals.[UniProtKB:Q9C000] Regulatory part that prevents formation of the Nlrp1a inflammasome: in absence of pathogens and other damage-associated signals, interacts with the C-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, C-terminus), preventing activation of the Nlrp1a inflammasome. In response to pathogen-associated signals, this part is ubiquitinated by the N-end rule pathway and degraded by the proteasome, releasing the cleaved C-terminal part of the protein, which polymerizes and forms the Nlrp1a inflammasome.[UniProtKB:Q9C000] Constitutes the active part of the Nlrp1a inflammasome (PubMed:33731929). In absence of pathogens and other damage-associated signals, interacts with the N-terminal part of Nlrp1a (NACHT, LRR and PYD domains-containing protein 1a, N-terminus), preventing activation of the Nlrp1a inflammasome. In response to pathogen-associated signals, the N-terminal part of Nlrp1a is degraded by the proteasome, releasing this form, which polymerizes to form the Nlrp1a inflammasome complex: the Nlrp1a inflammasome complex then directly recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, leading to gasdermin-D (GSDMD) cleavage and subsequent pyroptosis.[UniProtKB:Q9C000]^[4]

References

1. ↑ Newman ZL, Printz MP, Liu S, Crown D, Breen L, Miller-Randolph S, Flodman P, Leppla SH, Moayeri M. Susceptibility to anthrax lethal toxin-induced rat death is controlled by a single chromosome 10 locus that includes rNlrp1. PLoS Pathog. 2010 May 20;6(5):e1000906. PMID:20502689 doi:10.1371/journal.ppat.1000906
2. ↑ Gai K, Okondo MC, Rao SD, Chui AJ, Ball DP, Johnson DC, Bachovchin DA. DPP8/9 inhibitors are universal activators of functional NLRP1 alleles. Cell Death Dis. 2019 Aug 5;10(8):587. PMID:31383852 doi:10.1038/s41419-019-1817-5
3. ↑ Huang M, Zhang X, Toh GA, Gong Q, Wang J, Han Z, Wu B, Zhong F, Chai J. Structural and biochemical mechanisms of NLRP1 inhibition by DPP9. Nature. 2021 Apr;592(7856):773-777. PMID:33731929 doi:10.1038/s41586-021-03320-w
4. ↑ Huang M, Zhang X, Toh GA, Gong Q, Wang J, Han Z, Wu B, Zhong F, Chai J. Structural and biochemical mechanisms of NLRP1 inhibition by DPP9. Nature. 2021 Apr;592(7856):773-777. PMID:33731929 doi:10.1038/s41586-021-03320-w
5. ↑ Huang M, Zhang X, Toh GA, Gong Q, Wang J, Han Z, Wu B, Zhong F, Chai J. Structural and biochemical mechanisms of NLRP1 inhibition by DPP9. Nature. 2021 Apr;592(7856):773-777. PMID:33731929 doi:10.1038/s41586-021-03320-w